Lyme disease (LD) is the most prevalent vector-borne disease in the United States, with up to 300,000 cases a year. LD is caused by several species of the spirochete bacteria Borrelia burgdorferi sensu lato (the Lyme borreliae), which are transmitted by ticks from animal (bird, rodent) reservoirs to human hosts. While a short course of antibiotics is usually effective in eliminating the bacteria a sizeable number of LD patients continue to suffer long-term, debilitating sequelae, including pain, fatigue, cognitive dysfunction and other symptoms known as post-treatment Lyme disease (PTLD). As many as 1.9 million people in the US suffer from PTLD. There is currently no vaccine that can prevent LD or PTLD. We are developing an immunoprophylactic for LD and other tick-borne diseases (TBD) based on an understanding of the virulence mechanisms that the causal pathogens use to evade innate immunity. These pathogens protect themselves from elimination by the human complement system by binding to the human complement inhibitor Factor H (FH), a protein abundant in blood. FH bound to bacterial surfaces blocks the activation of the alternative complement pathway that would otherwise destroy the bacteria. We have produced recombinant proteins that are fusions of the FH domains that bind to Lyme borreliae with the constant region of human IgG1 (Fc), using a plant expression system. These fusion proteins (SCR6,7/Fc and SCR(18-20)/Fc) bind to Lyme borreliae and, in the presence of human complement, kill the bacteria. The Fc gives the proteins a long half-life, which may allow them to be used as a pre-exposure prophylactic (PrEP) to prevent LD and TBDs. The overall goal of this Phase I SBIR is to demonstrate the efficacy of SCR6,7/Fc and SCR(18-20)/Fc in preventing Lyme borreliae infection in a mouse model of LD and determine a minimal effective dose. The project is a collaboration of three research groups that are uniquely qualified to bring it to a successful conclusion. Planet Biotechnology (the small business concern) will produce SCR6,7/Fc and SCR(18-20)/Fc and two novel Fc variants of both proteins designed to enhance complement activation. Catherine Brissette at the University of North Dakota will evaluate the ability of the proteins to mediate complement-dependent killing of Lyme and relapsing fever spirochetes by membrane attack complex and opsonophagocytosis by human macrophages. Yi- Pin Lin at the New York State Department of Health will evaluate the ability of the proteins to block infection when mice are bitten by ticks carrying a virulent Lyme borreliae strain. The mouse experiments are designed to both identify the most potent SCR6,7/Fc and SCR(18-20)/Fc variant and identify the minimal dose that is 100% effective in blocking infection when injected 1 day prior to tick challenge. If successful, we will have demonstrated the commercial potential of an FH/Fc fusion as a PrEP for LD and potentially other TBD.